Abstract 18322: Compensatory Accumulation of βHydroxybutyrate Accompanied by SCOT Downregulation in Failing Hearts

Background and Objective: Circulating levels of ketone bodies have been previously reported to be increased in patients with congestive heart failure (HF). Recent studies have shown that the ketone body βhydroxybutyrate (βOHB) acts not only as a carrier of energy but also as a signaling molecule that has a role in diverse cellular functions. In this study, we investigated regulatory mechanism and pathophysiological role of βOHB in HF. Methods and Results: Unexpectedly, despite the presence of cardiac dysfunction, circulating βOHB levels were not elevated in hamster model for dilated cardiomyopathy. However, we found that βOHB was increased in hearts as well as liver. Intriguingly, whereas the augmentation in hepatic ketogenesis did not even occur, hypertrophied hearts of mice subjected to aortic banding also showed an increase in levels of βOHB, indicating that the elevated myocardial βOHB was not accompanied by an increase in its delivery from the liver to the heart through the blood stream. Therefore, we sought to investigate the regulatory mechanisms of βOHB metabolism in failing hearts. The gene and protein expression levels of CoA transferase (SCOT), a key enzyme involved in ketone body oxidation, was decreased in hypertrophied hearts. Using rat neonatal ventricular cardiomyocytes, we also revealed that H 2 O 2 stimulation caused βOHB accumulation concomitantly with SCOT downregulation, implying that the accumulation of myocardial βOHB occurs because of the decline in its utilization. Finally, we checked the effects of βOHB on cardiomyocytes under oxidative stress. We found that βOHB induced FOXO3a, an oxidative stress resistance gene, and its target enzyme, SOD2 and catalase. Dihydroethidium staining revealed that βOHB attenuated reactive oxygen species production induced by H 2 O 2 stimulation. Moreover, pretreatment of βOHB alleviated apoptosis induced by oxidative stress. Conclusion: It has been reported that hyperadrenergic state in HF boost lipolysis and result in elevation of circulating free fatty acids, which can lead hepatic ketogenesis for energy metabolism alteration. The present findings suggest that the accumulation of myocardial βOHB also occurs as a compensatory response against oxidative stress.